CD45 is a hematopoietic cell-specific transmembrane protein tyrosine phosphatase essential for T and B cell antigen receptor-mediated signaling and also plays a important role in cytokine receptor signaling, chemokine and cytokine response and apoptosis regulation in multiple different leukocyte cell subsets (T cells, B cells, NK cells, myeloid cells, granulocytes, and dendritic cells). CD45 constitutes nearly 10% of T and B cell surface protein. The protein includes a large extracellular domain, and a phosphatase containing cytosolic domain. CD45 may act as both a positive and negative regulator depending on the nature of the stimulus and the cell type involved. CD45 RNA transcripts are alternatively spliced at the N-terminus, which results in extracellular domains of various sizes. The protein controls the activity of Src-family kinases, which if left unregulated, can cause cancer and autoimmunity. Mice and humans lacking CD45 expression have been shown to be immunodeficient.
Multiple human or rodent mutations that result in altered CD45 expression or functional activity are associated with distinct malignancies, including autoimmunity, immunodeficiency, overt activation of T cells, susceptibility to infection, type I or type II associated immune disorders, and haemotologic malignancies (reviewed in Tchilian and Beverly, Trends in Immunology, 2006).
Double-stranded RNA molecules (dsRNA) have been shown to block gene expression in a highly conserved regulatory mechanism known as RNA interference (RNAi). WO 99/32619 (Fire et al.) discloses the use of a dsRNA of at least 25 nucleotides in length to inhibit the expression of the unc-22 gene in C. elegans. dsRNA has also been shown to degrade target RNA in other organisms, including plants (see, e.g., WO 99/53050, Waterhouse et al.; and WO 99/61631, Heifetz et al.), Drosophila (see, e.g., Yang, D., et al., Curr. Biol. (2000) 10:1191-1200), and mammals (see WO 00/44895, Limmer; and DE 101 00 586.5, Kreutzer et al.).